This invention relates to sulfur containing dihydrophthalazine compounds useful as antagonists of excitatory amino acid receptors.
During the past twenty-five years a great deal of attention has been directed toward the excitatory amino acids (EAA""s), glutamate and aspartate, since they are believed to be the neurotransmitters responsible for the fast excitatory transmission in the mammalian central nervous system. The ionotropic EAA receptors are generally sub-classified into NMDA and non-NMDA receptors. These classifications are defined by those receptors which preferentially bind N-methyl-D-aspartate (NMDA) and those that are not responsive to NMDA but responsive to xcex1-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) or kainic acid (KA).
Tarnawa et al, describe 2,3-benzodiazepines (Eur. J. Pharmacol., 167:193-199, 1989) which inhibit AMPA stimulated currents in neuronal cells. The 2,3-benzodiazepines such as GYKI 52466 and 53655 described by Tarnawa are non-competitive AMPA antagonists which bind to a novel modulatory site on the AMPA receptor. Meldrum (Stroke, 23:861, 1992 and Brain Res., 571:115, 1992) has shown that GYKI 52466 is effective in rat models of both global and focal ischemia. GYKI 52466 was effective in a middle cerebral artery occlusion (MCAO) model of ischemia when given either continuously for 2 hours just after occlusion or delayed for one hour. The compounds reduced cortical infarct volumes by 68% and 48% respectively. In another model of neurodegenerative disease, GYKI 52466 was as effective as the glutamate site competitive antagonist NBQX in rat common carotid arteries model of global ischemia.
These two animal models suggest that these compounds may be useful for the treatment of stroke and neurodegenerative ischemic conditions.
Efforts to find NMDA receptor antagonists and blockers which are neuroprotective have been very successful while efforts to find specific non-NMDA receptor antagonists have been much less successful. A number of pharmaceutical companies have pursued development of ion channel blockers or full antagonists of the NMDA receptor to protect against both chronic and acute neurodegenerative processes. Although some compounds have entered clinical trials, there has been only limited progress in developing a clinically useful NMDA receptor antagonist. Some useful compounds, namely substituted dihydrophthalazines, have been described for use as non-NMDA receptor antagonists (U.S. Pat. No. 5,716,956). These compounds are particularly useful because they bind to KA and/or AMPA receptors directly.
It is an object of the invention to provide compounds which are useful as non-NMDA glutamate receptor antagonists as well as methods for their synthesis.
It is a further object of the invention to provide non-NMDA receptor antagonists which are useful as sedatives or for the treatment of neuropsychopharmacological disorders such as stroke, ischemia and epilepsy.
It is yet another object of the invention to provide compounds which are useful for the treatment of neurological, neuropsychiatric, neurogenerative and functional disorders associated with excessive activation of the non-NMDA subtypes of the ionotropic EAA receptor.
Compositions are provided which are active as non-NMDA ionotropic excitatory amino acid (EAA) receptor antagonists, in particular, which bind to the KA and/or AMPA receptors, and which therefore are useful for treating disorders associated with excessive activation of the non-NMDA subtypes of the ionotropic EAA receptors. The compounds further are useful as testing agents to identify and characterize other compounds for the treatment of these disorders.
Illustrative compounds include:
4-(4-Aminophenyl)-1,2-dihydro-1-methyl-2-ethylcarbamoyl-6-methylthiophthalazine,
4-(4-Aminophenyl)-1,2-dihydro-1-methyl-2-n-propylcarbamoyl-6-methylthiophthalazine,
4-(4-Aminophenyl)-1,2-dihydro-1-methyl-2-n-butylcarbamoyl-6-methylthiophthalazine,
4-(4-Aminophenyl)-1,2-dihydro-2-ethylcarbamoyl-6-methylthiophthalazine,
4-(4-Aminophenyl)-1,2-dihydro-2-n-propylcarbamoyl-6-methylthiophthalazine,
4-(4-Aminophenyl)-1,2-dihydro-2-n-butylcarbamoyl-6-methylthiophthalazine.
The compositions may be provided in combination with a suitable carrier for oral or parenteral administration. The compounds may be administered orally or parenterally for the treatment of a variety of disorders associated with non-NMDA glutamate receptor function. The compositions may be used, for example, as sedatives or for the treatment of neuropsychopharmacological disorders such as stroke, ischemia and epilepsy.